There is a high degree of co-morbidity between drug addiction and other mental illnesses. Adolescence is a critical period for the onset of substance use disorders as well as that of mood disorders, schizophrenia, and anxiety disorders. Insults that occur during adolescent brain maturation, such as stress exposure, may enhance vulnerability to drug experimentation and on-going use and the subsequent development of addiction; similar relationships with stress exposure have been found for other mental illnesses. Persons with dual diagnoses often exhibit symptoms that are more severe, persistent, and resistant to treatment, in comparison to patients who have either disorder alone. Nonetheless, effective medications that address both conditions for these dual diagnosis (or co-morbid) populations have not been well established. There have been a limited number of preclinical models for co-morbid conditions. Given that preclinical models are useful to better understand neurobiological mechanisms of, and explore novel therapeutic strategies for brain disorders, further studies are warranted. We have recently reported a model that displays depression-associated behavioral alterations as well as molecular changes in dopaminergic pathways (Niwa et al, Science 2013): we observed mesocortical projection-specific epigenetic changes in the dopaminergic neurons in a glucocorticoid signaling-related manner. We have further expanded our preliminary study with additional data on abnormal responses to cocaine. On the basis of these two independent observations, we hypothesize that this disease model may be useful for studying the neurobiology of co-morbid cocaine addiction and depression, by making additional protocol changes in cocaine exposure and further optimization. First, we plan to establish a model that displays co-morbid phenotypes of aberrant response to cocaine and depression-relevant behaviors, and plan to use it to develop neurobiological mechanisms of co-morbid drug addiction and mental illness. Second, we will identify a way of intervening with the co-morbid conditions in the disease model with cocaine exposure. Using techniques already established in our group, we propose to study projection-specific effects of the hypothalamic-pituitary-adrenal axis on dopaminergic neurons and behavior in the model of co-morbidity. A successful completion of these studies will broaden our understanding of co-morbid conditions. Once we establish a model that displays the co-morbid phenotypes, the model will be useful for studying pathological mechanisms underlying such co-morbid conditions. The model will also provide a good template not only for screening compounds with better efficacy and fewer side effects, but also for prophylactic environmental readjustment, which is crucially important in clinical psychiatry.